The urinary bladder is a hollow, elastic organ that collects urine produced by the kidneys prior to urination (also referred to as “voiding” or “micturition”). The wall of the bladder generally includes an inner mucosal layer, a submucosal layer, and a muscular layer comprising, from inside-out, inner longitudinal, circular and outer longitudinal sublayers. Over the muscular layer are one or more connective tissue layers referred to as the serosa and adventitia. Between the bladder and the urethra is at least one bladder sphincter (the external bladder sphincter) that regulates the flow of urine from the bladder into the urethra during urination.
Contraction and relaxation of the bladder sphincter(s), and contraction of the bladder wall (also referred to as the “detrusor muscle”) are controlled by both somatic and autonomic nervous systems and, on the autonomic side, by both the sympathetic and parasympathetic nervous systems. Sensory information from stretch receptors within the muscular layer of the bladder is conveyed by sensory afferents extending from the bladder to the pons, while efferent connections extend from the pons to the bladder by way of the pelvic nerve (parasympathetic) and/or the hypogastric nerve (sympathetic). Somatic control over voiding is mediated by the pudendal nerve, which innervates the external bladder sphincter and controls voluntary sphincter contraction and relaxation.
While normal bladder activity is easy to take for granted, it is an essential part of human physiology. Normal adults generally urinate around 6 or 7 times a day, typically during waking hours, though the frequency and timing of voiding can vary significantly between individuals. Overactive bladder (“OAB”) is a condition in which normal voiding rhythm is disrupted, which is characterized by four symptoms: first, increased urgency to urinate, defined formally as a sudden, compelling desire to urinate that is difficult to deter; second, abnormal urinary frequency, defined as urination more than eight times per day; third, interruption of normal sleep by the urge to void, referred to as “nocturia;” and fourth, “urge incontinence” or involuntary voiding of the bladder during periods of urinary urgency. In the United States, OAB affects an estimated 16% of adults, and about 6% of adults suffer from OAB characterized by urge incontinence. (See Stewart W F, et al. Prevalence and burden of overactive bladder in the United States. World J Urol. May 20, 2003; (6):327-36.)
OAB has a variety of potential causes which are generally classified as myogenic (arising in the smooth muscle of the bladder), neuropathic (arising from the nervous system), mixed, or idiopathic (lacking a clear etiology). Notwithstanding these categorizations, electrical changes including increased spontaneous contractility and greater electrical coupling between myocytes are observed in detrusor muscle samples taken from patients with both neuropathic and non-neuropathic OAB.
Current treatments for OAB include behavioral therapy to include control over urgency and/or to improve bladder capacity; pharmacotherapy with anticholinergic drugs (e.g. darifenacin, fesoterdione, oxybutynin, etc.) or neurotoxins (e.g. onabotulinumtoxin-A); and electrical neuromodulation of the sacral nerve (for instance, using the InterStim® neuromodulator device (Medtronic, Inc. Minneapolis, Minn.)). While these interventions may be effective to treat OAB in some patients, current pharmacotherapies require repeated administration, while both pharmacological and neuromodulation approaches offer systemic, rather than targeted, intervention, and are accompanied by an increased risk of side effects.